Thienopyrimidinone nmda receptor modulators and uses thereof

ABSTRACT

Disclosed herein, in part, are heteroaromatic compounds and methods of use in treating neuropsychiatric disorders, e.g., schizophrenia and major depressive disorder. Pharmaceutical compositions and methods of making heteroaromatic compounds are provided. The compounds are contemplated to modulate the NMDA receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/265,187, filed Dec. 9, 2015, hereby incorporated by reference inits entirety.

BACKGROUND

Diseases of the nervous system are collectively the leading cause ofhuman disability, as measured by the global burden of disease. Eventhose major diseases of the nervous system for which treatments havebeen approved by health authorities, including psychiatric diseases suchas Schizophrenia, neurological diseases such as Alzheimer's Disease, andneurodevelopmental disorders, such as Attention Deficit andHyperactivity Disorder, are poorly managed because approved treatmentshave limited efficacy and serious side effects, leaving a significantburden of unmet medical need. In addition, there are many major and rarenervous system disorders for which no treatments are approved, such asthe neurodevelopmental disorders of the Autism Spectrum, and manyintellectual disability disorders, and which are therefore associatedwith profound unmet medical need.

The N-methyl-D-aspartate-(NMDA) subtype of ligand-gated ion channelreceptors are a diverse family of glutamate receptors widely accepted tomediate synaptic transmission, key mechanisms of synaptic plasticity,and dynamic neuronal network connectivity required for normal nervoussystem development and function.

The NMDA receptor is composed of four protein subunits, two GluN1subunits and two GluN2 subunits. The GluN1 subunit is derived from asingle gene (GRIN1), is ubiquitously expressed throughout the nervoussystem, and is common to all NMDA receptors. Four different GluN2subunits, GluN2A-D, are derived from separate genes (GRIN2A-D) that aredifferentially expressed in different regions of the nervous system andby distinct populations of neurons within a particular region. A GluN3subunit has also been identified, but its function is less wellunderstood. Furthermore, individual neurons may express more than oneGluN2 subunit and individual NMDA receptors expressed by such neuronsmay contain two of the same GluN2 subunits (for example, 2GluN2Bsubunits) or two different subunits (one GluN2A and one GluN2B subunit).In addition, all NMDA receptor subunits are expressed as diverse mRNAsplice variants. Thus, native nervous system NMDA receptors are highlydiverse in their composition.

The study of the molecular basis of NMDA receptor function continues tobe an area of importance. As glutamate is the major excitatoryneurotransmitter, dysfunction of glutamate neurotransmission and NMDAreceptor-dependent mechanisms of synaptic transmission, plasticity, andneuronal network connectivity are broadly implicated in diseases of thenervous system. Accordingly, compounds that are capable of modulatingNMDA receptors may be useful for the treatment of nervous systemdisorders and diseases, for example, schizophrenia, Alzheimer's disease,attention deficit and hyperactivity disorder, and autism.

SUMMARY

The present disclosure provides, for example, compounds which aremodulators of NMDA receptors (e.g., positive allosteric modulators ofNMDA receptors) and their use as medicinal agents, processes for theirpreparation, and pharmaceutical compositions containing them as anactive ingredient. The disclosure provides for the use of disclosedcompounds as medicaments and/or in the manufacture of medicaments forthe modulation of NMDA receptors in warm-blooded animals such as humans.In particular this disclosure relates to compounds useful for thetreatment of psychiatric, neurologicial and/or neurodevelopmentaldisorders and/or diseases of the nervous system, for example,schizophrenia, Alzheimer's disease, attention deficit and hyperactivity,autism, and other nervous system-associated conditions. Also providedare pharmaceutical compositions comprising at least one disclosedcompound and a pharmaceutically acceptable carrier.

In an embodiment, provided herein are compounds represented by FormulaI:

and pharmaceutically acceptable salts, stereoisomers and prodrugsthereof, wherein R¹, R², R³, R⁶⁶, R⁶⁷ and n are as defined herein.

DETAILED DESCRIPTION

The features and other details of the disclosure will now be moreparticularly described. Before further description of the presentinvention, certain terms employed in the specification, examples andappended claims are collected here. These definitions should be read inlight of the remainder of the disclosure and as understood by a personof skill in the art. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by a person of ordinary skill in the art.

Definitions

“Treating” includes any effect, e.g., lessening, reducing, modulating,or eliminating, that results in the improvement of the condition,disease, disorder and the like.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon. Exemplary alkyl groups include, but are notlimited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbonatoms, referred to herein as C₁₋₆alkyl, C₁₋₄alkyl, and C₁₋₃alkyl,respectively. Exemplary alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond.Exemplary alkenyl groups include, but are not limited to, a straight orbranched group of 2-6 or 3-4 carbon atoms, referred to herein asC₂₋₆alkenyl, and C₃₋₄alkenyl, respectively. Exemplary alkenyl groupsinclude, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

The term “alkoxy” as used herein refers to a straight or branched alkylgroup attached to oxygen (alkyl-O—). Exemplary alkoxy groups include,but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms,referred to herein as C₁₋₆alkoxy, and C₂₋₆alkoxy, respectively.Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy,isopropoxy, etc.

The term “alkylcarbonyl” as used herein refers to a straight or branchedalkyl group attached to a carbonyl group (alkyl-C(O)—). Exemplaryalkylcarbonyl groups include, but are not limited to, alkylcarbonylgroups of 1-6 atoms, referred to herein as C₁₋₆alkylcarbonyl groups.Exemplary alkylcarbonyl groups include, but are not limited to, acetyl,propanoyl, isopropanoyl, butanoyl, etc.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond.Exemplary alkynyl groups include, but are not limited to, straight orbranched groups of 2-6, or 3-6 carbon atoms, referred to herein asC₂₋₆alkynyl, and C₃₋₆alkynyl, respectively. Exemplary alkynyl groupsinclude, but are not limited to, ethynyl, propynyl, butynyl, pentynyl,hexynyl, methylpropynyl, etc.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “cyano” as used herein refers to the radical —CN.

The terms “cycloalkyl” or a “carbocyclic group” as used herein refers toa saturated or partially unsaturated hydrocarbon group of, for example,3-6, or 4-6 carbons, referred to herein as C₃₋₆cycloalkyl orC₄₋₆cycloalkyl, respectively. Exemplary cycloalkyl groups include, butare not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutylor cyclopropyl.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to oxygen (cycloalkyl-O—). Exemplary cycloalkoxy groupsinclude, but are not limited to, cycloalkoxy groups of 3-6 carbon atoms,referred to herein as C₃₋₆cycloalkoxy groups. Exemplary cycloalkoxygroups include, but are not limited to, cyclopropoxy, cyclobutoxy,cyclohexyloxy, etc.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The terms “heteroaryl” or “heteroaromatic group” as used herein refersto a monocyclic aromatic 5-6 membered ring system containing one or moreheteroatoms, for example one to three heteroatoms, such as nitrogen,oxygen, and sulfur. Where possible, said heteroaryl ring may be linkedto the adjacent radical though carbon or nitrogen. Examples ofheteroaryl rings include but are not limited to furan, thiophene,pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole,triazole, pyridine or pyrimidine etc.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized andrefer to saturated or partially unsaturated, 4-10 membered ringstructures, including bridged or fused rings, and whose ring structuresinclude one to three heteroatoms, such as nitrogen, oxygen, and sulfur.Where possible, heterocyclyl rings may be linked to the adjacent radicalthrough carbon or nitrogen. Examples of heterocyclyl groups include, butare not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine,piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc.

The term “heterocyclyloxy” as used herein refers to a heterocyclyl groupattached to oxygen (heterocyclyl-O—).

The term “heteroaryloxy” as used herein refers to a heteroaryl groupattached to oxygen (heteroaryl-O—).

The terms “hydroxy” and “hydroxyl” as used herein refers to an OHfunctionality.

The term “oxo” as used herein refers to a carbonyl functionality (e.g.,C═O).

“Pharmaceutically or pharmacologically acceptable” include molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. For human administration, preparations should meetsterility, pyrogenicity, and general safety and purity standards asrequired by FDA Office of Biologics standards.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein refers to any and all solvents,dispersion media, coatings, isotonic and absorption delaying agents, andthe like, that are compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. The compositions may also contain other activecompounds providing supplemental, additional, or enhanced therapeuticfunctions.

The term “pharmaceutical composition” as used herein refers to acomposition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

“Individual,” “patient,” or “subject” are used interchangeably andinclude any animal, including mammals, preferably mice, rats, otherrodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates,and most preferably humans. The compounds of the invention can beadministered to a mammal, such as a human, but can also be administeredto other mammals such as an animal in need of veterinary treatment,e.g., domestic animals (e.g., dogs, cats, and the like), farm animals(e.g., cows, sheep, pigs, horses, and the like) and laboratory animals(e.g., rats, mice, guinea pigs, and the like). The mammal treated in themethods of the invention is desirably a mammal in which treatment ofe.g., schizophrenia desired. “Modulation” includes antagonism (e.g.,inhibition), agonism, partial antagonism and/or partial agonism.

In the present specification, the term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system or animal, (e.g.mammal or human) that is being sought by the researcher, veterinarian,medical doctor or other clinician. The compounds of the invention areadministered in therapeutically effective amounts to treat a disease.Alternatively, a therapeutically effective amount of a compound is thequantity required to achieve a desired therapeutic and/or prophylacticeffect, such as an amount which results in substantially relief ofsymptoms associated with schizophrenia.

The term “pharmaceutically acceptable salt(s)” as used herein refers tosalts of acidic or basic groups that may be present in compounds used inthe compositions. Compounds included in the present compositions thatare basic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including, but notlimited to, malate, oxalate, chloride, bromide, iodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.Compounds included in the present compositions that are acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include alkali metal oralkaline earth metal salts, particularly calcium, magnesium, sodium,lithium, zinc, potassium, and iron salts. Compounds included in thepresent compositions that include a basic or acidic moiety may also formpharmaceutically acceptable salts with various amino acids. Thecompounds of the disclosure may contain both acidic and basic groups;for example, one amino and one carboxylic acid group. In such a case,the compound can exist as an acid addition salt, a zwitterion, or a basesalt.

The compounds of the disclosure may be chiral or exist as stereoisomers.The term “stereoisomers” when used herein consist of all enantiomers ordiastereomers. These compounds may be designated by the symbols “(+),”“(−),” “R” or “S,” depending on the configuration of substituents aroundthe stereogenic carbon atom, but the skilled artisan will recognize thata structure may denote a stereogenic center implicitly. The presentinvention encompasses various stereoisomers of these compounds andmixtures thereof. Mixtures of enantiomers or diastereomers may bedesignated “(+)” in nomenclature, but the skilled artisan will recognizethat a structure may denote a stereogenic center implicitly.

The compounds of the disclosure may contain one or more double bondsand, therefore, exist as geometric isomers resulting from thearrangement of substituents around a carbon-carbon double bond. Thesymbol

denotes a bond that may be a single, double or triple bond as describedherein. Substituents around a carbon-carbon double bond are designatedas being in the “Z” or “E” configuration wherein the terms “Z” and “E”are used in accordance with IUPAC standards. Unless otherwise specified,structures depicting double bonds encompass both the “E” and “Z”isomers. Substituents around a carbon-carbon double bond alternativelycan be referred to as “cis” or “trans,” where “cis” representssubstituents on the same side of the double bond and “trans” representssubstituents on opposite sides of the double bond.

Compounds of the disclosure may contain a carbocyclic or heterocyclicring and therefore, exist as geometric isomers resulting from thearrangement of substituents around the ring. The arrangement ofsubstituents around a carbocyclic or heterocyclic ring are designated asbeing in the “Z” or “E” configuration wherein the terms “Z” and “E” areused in accordance with IUPAC standards. Unless otherwise specified,structures depicting carbocyclic or heterocyclic rings encompass both“Z” and “E” isomers. Substituents around a carbocyclic or heterocyclicrings may also be referred to as “cis” or “trans”, where the term “cis”represents substituents on the same side of the plane of the ring andthe term “trans” represents substituents on opposite sides of the planeof the ring. Mixtures of compounds wherein the substituents are disposedon both the same and opposite sides of plane of the ring are designated“cis/trans.”

Individual enantiomers and diasteriomers of compounds of the presentinvention can be prepared synthetically from commercially availablestarting materials that contain asymmetric or stereogenic centers, or bypreparation of racemic mixtures followed by resolution methods wellknown to those of ordinary skill in the art. These methods of resolutionare exemplified by (1) attachment of a mixture of enantiomers to achiral auxiliary, separation of the resulting mixture of diastereomersby recrystallization or chromatography and liberation of the opticallypure product from the auxiliary, (2) salt formation employing anoptically active resolving agent, (3) direct separation of the mixtureof optical enantiomers on chiral liquid chromatographic columns or (4)kinetic resolution using stereoselective chemical or enzymatic reagents.Racemic mixtures can also be resolved into their component enantiomersby well known methods, such as chiral-phase liquid chromatography orcrystallizing the compound in a chiral solvent. Stereoselectivesyntheses, a chemical or enzymatic reaction in which a single reactantforms an unequal mixture of stereoisomers during the creation of a newstereocenter or during the transformation of a pre-existing one, arewell known in the art. Stereoselective syntheses encompass both enantio-and diastereoselective transformations, and may involve the use ofchiral auxiliaries. For examples, see Carreira and Kvaerno, Classics inStereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

The compounds disclosed herein can exist in solvated as well asunsolvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. In one embodiment, thecompound is amorphous. In one embodiment, the compound is a singlepolymorph. In another embodiment, the compound is a mixture ofpolymorphs. In another embodiment, the compound is in a crystallineform.

The invention also embraces isotopically labeled compounds of theinvention which are identical to those recited herein, except that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. For example,a compound of the invention may have one or more H atom replaced withdeuterium.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in the examples herein by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

The term “prodrug” refers to compounds that are transformed in vivo toyield a disclosed compound or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvarious mechanisms (such as by esterase, amidase, phosphatase, oxidativeand or reductive metabolism) in various locations (such as in theintestinal lumen or upon transit of the intestine, blood or liver).Prodrugs are well known in the art (for example, see Rautio,Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). Forexample, if a compound of the invention or a pharmaceutically acceptablesalt, hydrate or solvate of the compound contains a carboxylic acidfunctional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁₋₈)alkyl, (C₂₋₁₂)alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethylhaving from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁₋₂)alkylamino(C₂₋₃)alkyl (such as (3-dimethylaminoethyl),carbamoyl-(C₁₋₂)alkyl, N,N-di(C₁₋₂)alkylcarbamoyl-(C₁₋₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂₋₃)alkyl.

Similarly, if a compound of the invention contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as (C₁₋₆)alkylcarbonyloxymethyl,1-((C₁₋₆)alkylcarbonyloxy)ethyl,1-methyl-1-((C₁₋₆)alkylcarbonyloxy)ethyl (C₁₋₆)alkoxycarbonyloxymethyl,N—(C₁₋₆)alkoxycarbonylaminomethyl, succinoyl, (C₁₋₆)alkylcarbonyl,α-amino(C₁₋₄)alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl,or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl, where eacht-aminoalkylcarbonyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

If a compound of the invention incorporates an amine functional group, aprodrug can be formed, for example, by creation of an amide orcarbamate, an N-alkylcarbonyloxyalkyl derivative, an(oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine.In addition, a secondary amine can be metabolically cleaved to generatea bioactive primary amine, or a tertiary amine can metabolically cleavedto generate a bioactive primary or secondary amine. For examples, seeSimplicio, et al., Molecules 2008, 13, 519 and references therein.

I. Heteroaromatic Compounds

In certain embodiments, the present disclosure provides compounds ofFormula I

and pharmaceutically acceptable salts, stereoisomers and prodrugsthereof, wherein:

n is 1 or 2;

R¹ and R² are each independently selected from the group consisting ofhydrogen, halogen, hydroxyl, NR^(a)R^(b), C₁₋₄ alkyl, C₃₋₆cycloalkyl,C₁₋₄alkoxy, and C₃₋₆cycloalkoxy; wherein C₁₋₄ alkyl, C₃₋₆cycloalkyl,C₁₋₄alkoxy, and C₃₋₆cycloalkoxy may be optionally substituted with one,two or three substituents each independently selected from halogen,hydroxyl, cyano, and NR^(a)R^(b); or

R¹ and R², together with the carbon to which they are attached form:

-   -   a 4-6 membered saturated heterocyclic ring having one or two        heteroatoms selected from the group consisting of O, S(O)_(w)        (wherein w is 0, 1 or 2) and NR^(a); or    -   a 3-6 membered saturated carbocyclic ring;    -   wherein the heterocyclic ring may optionally be substituted on        carbon by one, two or more substituents each selected from the        group consisting of phenyl (optionally substituted by one, two        or three halogens), C₃-C₆cycloalkyl (optionally substituted by        one, two or three halogens), C₁₋₆alkoxy (optionally substituted        by one, two or three halogens), C₁₋₆alkyl (optionally        substituted by one, two or three halogens), and oxo; and on a        carbon that is not bound to a heteroatom, by halogen, cyano,        —NR^(a)R^(b) and hydroxyl; and    -   the carbocyclic ring may optionally be substituted by one, two        or more substituents each selected from the group consisting of:        phenyl (optionally substituted by one, two or three halogens),        C₃-C₆cycloalkyl (optionally substituted by one, two or three        halogens), C₁₋₆alkoxy (optionally substituted by one, two or        three halogens), C₁₋₆alkyl (optionally substituted by one, two        or three halogens), oxo, halogen, cyano, —NR^(a)R^(b) and        hydroxyl;

R³ is selected from the group consisting of phenyl, naphthyl,heteroaryl, heterocyclyl and C₃₋₆cycloalkyl; wherein R³ may optionallybe substituted with one, two or three substituents each independentlyselected from C₁₋₄alkyl, halogen, hydroxyl, cyano, C₁₋₄alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂₋, NR^(a)R^(b), C(O)OH,C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl; and wherein C₁₋₄alkyl,C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,and C₁₋₆alkylcarbonyl may be optionally substituted by one or moresubstituents each independently selected from halogen, hydroxyl, cyano,and NR^(a)R^(b);

R⁶⁶ and R⁶⁷ are each independently selected from the group consisting ofhydrogen, halogen, C₁₋₄alkyl (optionally substituted by one, two, threesubstituents selected from halogen, hydroxyl, cyano and NR^(a)R^(b)),and phenyl (optionally substituted by one, two or three halogens); and

R^(a) and R^(b) are independently selected, for each occurrence, fromthe group consisting of hydrogen and C₁₋₃alkyl; or R^(a) and R^(b),together with the nitrogen to which they are attached, form a 4-6membered heterocyclic ring which may have an additional heteroatomselected from O, S, or N.

In some embodiments of Formula I, n may be 1. In other or additionalembodiments, R¹ and R² may each be independently selected from the groupconsisting of hydrogen, halogen, C₁₋₃alkyl, and C₁₋₃alkoxy; whereinC₁₋₃alkyl and C₁₋₃alkoxy may optionally be substituted by one, two orthree halogens.

For example, R¹ and R² may each be independently selected from the groupconsisting of hydrogen, fluorine, C₁₋₃alkyl and methoxy; whereinC₁₋₃alkyl may optionally be substituted by one, two or three fluorineatoms.

In certain embodiments R³ may be selected from the group consisting ofphenyl and heteroaryl; wherein R³ may optionally be substituted withone, two or three substituents each independently selected from thegroup consisting of C₁₋₄alkyl, halogen, hydroxyl, cyano, C₁₋₄alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂₋, NR^(a)R^(b), C(O)OH,C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl; wherein C₁₋₄alkyl,C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,and C₁₋₆alkylcarbonyl may be optionally substituted by one or moresubstituents each independently selected from halogen, hydroxyl, cyano,and NR^(a)R^(b).

For example, R³ may be phenyl, pyrimidinyl, pyrazinyl or pyridinyl, eachoptionally substituted by one or two substituents each independentlyselected from the group consisting of halogen and C₁₋₃alkyl (optionallysubstituted by one, two or three halogens).

For example, R³ may be phenyl, optionally substituted by one, two orthree substituents each independently selected from the group consistingof fluorine, chlorine, bromine, CF₃, and C₁₋₄alkyl.

In other embodiments, a disclosed compound may be represented by:

wherein

R³³ is selected from the group consisting of fluorine, chlorine, CF₃ andmethyl; and wherein q is 0, 1, 2 or 3.

In certain embodiments, R⁶⁶ and R⁶⁷ may each be independently selectedfrom the group consisting of hydrogen and C₁₋₃alkyl; wherein C₁₋₃alkylmay optionally be substituted by one, two, or three halogens. Forexample, R⁶⁶ and R⁶⁷ may each be independently selected from the groupconsisting of hydrogen, methyl, and CF₃.

Also disclosed herein are compounds represented by Formula II:

and pharmaceutically acceptable salts, stereoisomers and prodrugsthereof, wherein:

R¹ and R² are each independently selected from the group consisting ofhydrogen, halogen, hydroxyl, NR^(a)R^(b), C₁₋₄ alkyl, C₃₋₆cycloalkyl,C₁₋₄alkoxy, and C₃₋₆cycloalkoxy; wherein C₁₋₄ alkyl, C₃₋₆cycloalkyl,C₁₋₄alkoxy, and C₃₋₆cycloalkoxy may be optionally substituted with one,two or three substituents each independently selected from halogen,hydroxyl, cyano, and NR^(a)R^(b);

R³ is selected from the group consisting of phenyl, naphthyl,heteroaryl, heterocyclyl and C₃₋₆cycloalkyl; wherein R³ may optionallybe substituted with one, two or three substituents each independentlyselected from C₁₋₄alkyl, halogen, hydroxyl, cyano, C₁₋₄alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂—, NR^(a)R^(b), C(O)OH,C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl; and wherein C₁₋₄alkyl,C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,and C₁₋₆alkylcarbonyl may be optionally substituted by one or moresubstituents each independently selected from halogen, hydroxyl, cyano,and NR^(a)R^(b);

R⁶⁶ and R⁶⁷ are each independently selected from the group consisting ofhydrogen, halogen, C₁₋₄alkyl (optionally substituted by one, two, threesubstituents selected from halogen, hydroxyl, cyano and NR^(a)R^(b)),and phenyl (optionally substituted by one, two or three halogens); and

R^(a) and R^(b) are independently selected, for each occurrence, fromthe group consisting of hydrogen and C₁₋₃alkyl; or R^(a) and R^(b),together with the nitrogen to which they are attached, form a 4-6membered heterocyclic ring which may have an additional heteroatomselected from O, S, or N.

In certain embodiments, R¹ and R² may each be independently selectedfrom the group consisting of hydrogen, halogen, C₁₋₃alkyl, andC₁₋₃alkoxy; wherein C₁₋₃alkyl and C₁₋₃alkoxy may optionally besubstituted by one, two or three halogens. For example, R¹ and R² mayeach be independently selected from the group consisting of hydrogen,fluorine, C₁₋₃alkyl and methoxy; wherein C₁₋₃alkyl may optionally besubstituted by one, two or three fluorine atoms.

In some embodiments, R³ may be selected from the group consisting ofphenyl and heteroaryl; wherein R³ may optionally be substituted withone, two or three substituents each independently selected from thegroup consisting of C₁₋₄alkyl, halogen, hydroxyl, cyano, C₁₋₄alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂—, NR^(a)R^(b), C(O)OH,C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl; wherein C₁₋₄alkyl,C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,and C₁₋₆alkylcarbonyl may be optionally substituted by one or moresubstituents each independently selected from halogen, hydroxyl, cyano,and NR^(a)R^(b).

In certain embodiments, R³ may be phenyl, pyrimidinyl, pyrazinyl orpyridinyl, each optionally substituted by one or two substituents eachindependently selected from the group consisting of halogen andC₁₋₃alkyl (optionally substituted by one, two or three halogens). Forexample, R³ may be phenyl, optionally substituted by one, two or threesubstituents each independently selected from the group consisting offluorine, chlorine, bromine, CF₃, and C₁₋₄alkyl.

In other embodiments, a disclosed compound may be represented by:

wherein

R³³ is selected from the group consisting of fluorine, chlorine, CF₃ andmethyl; and wherein q is 0, 1, 2 or 3.

In certain embodiments, R⁶⁶ and R⁶⁷ may each be independently selectedfrom the group consisting of hydrogen and C₁₋₃alkyl; wherein C₁₋₃alkylmay optionally be substituted by one, two, or three halogens. Forexample, R⁶⁶ and R⁶⁷ may each be independently selected from the groupconsisting of hydrogen, methyl, and CF₃.

Procedures for making compounds disclosed herein are provided below. Inthe reactions described below, it may be necessary to protect reactivefunctional groups (such as hydroxyl, amino, thio or carboxyl groups) toavoid their unwanted participation in the reactions. The incorporationof such groups, and the methods required to introduce and remove themare known to those skilled in the art (for example, see Greene, Wuts,Protective Groups in Organic Synthesis. 2nd Ed. (1999)). Thedeprotection step may be the final step in the synthesis such that theremoval of protecting groups affords compounds of Formula I. Startingmaterials used in the following schemes can be purchased or prepared bymethods described in the chemical literature, or by adaptations thereof,using methods known by those skilled in the art. The order in which thesteps are performed can vary depending on the groups introduced and thereagents used, but would be apparent to those skilled in the art.

Compounds of any of Formula I, as depicted above, or any of theintermediates described below, can be further derivatised by using oneor more standard synthetic methods known to those skilled in the art.Such methods can involve substitution, oxidation or reduction reactions.These methods can also be used to obtain or modify compounds of FormulaI or any preceding intermediates by modifying, introducing or removingappropriate functional groups. Particular substitution approachesinclude alkylation, arylation, heteroarylation, acylation,thioacylation, halogenation, sulfonylation, nitration, formylation,hydrolysis and coupling procedures. These procedures can be used tointroduce a functional group onto the parent molecule (such as thenitration or sulfonylation of aromatic rings) or to couple two moleculestogether (for example to couple an amine to a carboxylic acid to affordan amide; or to form a carbon-carbon bond between two heterocycles). Forexample, alcohol or phenol groups can be converted to ether groups bycoupling a phenol with an alcohol in a solvent (such as tetrahydrofuran)in the presence of a phosphine (such as triphenylphosphine) and adehydrating agent (such as diethyl, diisopropyl or dimethylazodicarboxylate). Alternatively, ether groups can be prepared bydeprotonation of an alcohol, using a suitable base (such as sodiumhydride) followed by the addition of an alkylating agent (such as analkyl halide or an alkyl sulfonate).

In another example, a primary or secondary amine can be alkylated usinga reductive alkylation procedure. For example, the amine can be treatedwith an aldehyde and a borohydride (such as sodiumtriacetoxyborohydride, or sodium cyanoborohydride in a solvent (such asa halogenated hydrocarbon, for example dichloromethane, or an alcohol,for example ethanol) and, where necessary, in the presence of an acid(such as acetic acid).

In another example, hydroxy groups (including phenolic OH groups) can beconverted into leaving groups, such as halogen atoms or sulfonyloxygroups (such as alkylsulfonyloxy, for exampletrifluoromethanesulfonyloxy, or aryl suphonyloxy, for examplep-toluenesulfonyloxy) using conditions known to those skilled in theart. For example, an aliphatic alcohol can be reacted with thionylchloride in a halogenated hydrocarbon (such as dichloromethane) toafford the corresponding alkyl chloride. A base (such as triethylamine)can also be used in the reaction.

In another example, ester groups can be converted to the correspondingcarboxylic acid group by acid- or base-catalysed hydrolysis depending onthe nature of the ester group. Acid catalysed hydrolysis can be achievedby treatment with an organic or inorganic acid (such as trifluoroaceticacid in an aqueous solvent, or a mineral acid such as hydrochloric acidin a solvent such as dioxane). Base catalysed hydrolysis can be achievedby treatment with an alkali metal hydroxide (such as lithium hydroxidein an aqueous alcohol, for example methanol).

In another example, aromatic halogen substituents in the compounds maybe subjected to halogen-metal exchange by treatment with a base (such asa lithium base, for example n-butyl or t-butyllithium) optionally at alow temperature (such as −78° C.) in a solvent (such as tetrahydrofuran)and the mixture may then be quenched with an electrophile to introduce adesired substituent. Thus, for example, a formyl group can be introducedby using dimethylformamide as the electrophile. Aromatic halogensubstituents can also be subjected to palladium catalysed reactions tointroduce groups such as carboxylic acids, esters, cyano or aminosubstituents.

In another example, an aryl, or heteroaryl ring substituted with anappropriate leaving group (such as a halogen or sulfonyl ester, forexample a triflate) can undergo a palladium catalysed coupling reactionwith a wide variety of substrates to form a carbon-carbon bond. Forexample, a Heck reaction can be used to couple such a ring system to analkene (which may, or may not, be further substituted) by treatment withan organopalladium complex (such astetrakis(triphenylphosphine)palladium(0), palladium (II) acetate orpalladium (II) chloride) in the presence of a ligand (such as aphosphine, for example triphenylphosphine) in the presence of a base(such as potassium carbonate or a tertiary amine, for example,triethylamine), in an appropriate solvent (such as tetrahydrofuran orDMF), under appropriate conditions (such as heating to, for example,50-120° C.). In another example, a Sonogashira reaction can be used tocouple such a ring system to an alkyne (which may, or may not be furthersubstituted) by treatment with a palladium complex (such astetrakis(triphenylphosphine)palladium(0)) and a halide salt of copper(I) (such as copper (I) iodide), in the presence of a base (such as apotassium carbonate or a tertiary amine, for example, triethylamine), inan appropriate solvent (such as tetrahydrofuran or dimethylformamide),under appropriate conditions (such as heating to, for example, 50-120°C.). In another example, a Stille reaction can be used to couple such aring system to an alkene, by treatment with an organotin compound (suchas an alkynyltin or alkenyltin reagent, for example analkenyltributylstannane) in the presence of a palladium complex (such astetrakis(triphenylphosphine)palladium(0)), with, or without the presenceof a salt (such as a copper (I) halide), in an appropriate solvent (suchas dioxane or dimethylformamide), under appropriate conditions (such asheating to, for example, 50-120° C.).

Particular oxidation approaches include dehydrogenations andaromatisation, decarboxylation and the addition of oxygen to certainfunctional groups. For example, aldehyde groups can be prepared byoxidation of the corresponding alcohol using conditions well known tothose skilled in the art. For example, an alcohol can be treated with anoxidising agent (such as Dess-Martin periodinane) in a solvent (such asa halogenated hydrocarbon, for example dichloromethane). Alternativeoxidising conditions can be used, such as treatment with oxalyl chlorideand an activating amount of dimethylsulfoxide and subsequent quenchingby the addition of an amine (such as triethylamine). Such a reaction canbe carried out in an appropriate solvent (such as a halogenatedhydrocarbon, for example dichloromethane) and under appropriateconditions (such as cooling below room temperature, for example to −78°C. followed by warming to room temperature). In another example, sulfuratoms can be oxidised to the corresponding sulfoxide or sulfone using anoxidising agent (such as a peroxy acid, for example3-chloroperoxybenzoic acid) in an inert solvent (such as a halogenatedhydrocarbon, for example dichloromethane) at around ambient temperature.

Particular reduction approaches include the removal of oxygen atoms fromparticular functional groups or saturation (or partial saturation) ofunsaturated compounds including aromatic or heteroaromatic rings. Forexample, primary alcohols can be generated from the corresponding esteror aldehyde by reduction, using a metal hydride (such as lithiumaluminium hydride or sodium borohydride in a solvent such as methanol).Alternatively, CH₂OH groups can be generated from the correspondingcarboxylic acid by reduction, using a metal hydride (such as lithiumaluminium hydride in a solvent such as tetrahydrofuran). In anotherexample, a nitro group may be reduced to an amine by catalytichydrogenation in the presence of a metal catalyst (such as palladium ona solid support such as carbon) in a solvent (such as an ether, forexample tetrahydrofuran, or an alcohol, such as methanol), or bychemical reduction using a metal (such as zinc, tin or iron) in thepresence of an acid (such as acetic acid or hydrochloric acid). In afurther example an amine can be obtained by reduction of a nitrile, forexample by catalytic hydrogenation in the presence of a metal catalyst(such as palladium on a solid support such as carbon), or Raney nickelin a solvent (such as tetrahydrofuran) and under suitable conditions(such as cooling to below room temperature, for example to −78° C., orheating, for example to reflux).

Salts of compounds of Formula I can be prepared by the reaction of acompound of Formula I with an appropriate acid or base in a suitablesolvent, or mixture of solvents (such as an ether, for example, diethylether, or an alcohol, for example ethanol, or an aqueous solvent) usingconventional procedures. Salts of compound of Formula I can be exchangedfor other salts by treatment using conventional ion-exchangechromatography procedures.

Where it is desired to obtain a particular enantiomer of a compound ofFormula I, this may be produced from a corresponding mixture ofenantiomers by employing any suitable conventional procedure forresolving enantiomers. For example, diastereomeric derivatives (such assalts) can be produced by reaction of a mixture of enantiomers of acompound of Formula I (such a racemate) and an appropriate chiralcompound (such as a chiral base). The diastereomers can then beseparated by any conventional means such as crystallisation, and thedesired enantiomer recovered (such as by treatment with an acid in theinstance where the diastereomer is a salt). Alternatively, a racemicmixture of esters can be resolved by kinetic hydrolysis using a varietyof biocatalysts (for example, see Patel Steroselective Biocatalysts,Marcel Decker; New York 2000).

In another resolution process a racemate of compounds of Formula I canbe separated using chiral High Performance Liquid Chromatography.Alternatively, a particular enantiomer can be obtained by using anappropriate chiral intermediate in one of the processes described above.Chromatography, recrystallisation and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular geometric isomer of the invention.

II. Methods

Another aspect of the disclosure provides methods of modulating theactivity of the NMDA receptor. Such methods may for example, compriseexposing said receptor to a compound described herein. In someembodiments, the compound utilized by one or more of the foregoingmethods is one of the generic, subgeneric, or specific compoundsdescribed herein, such as a compound of Formula I. The ability ofcompounds described herein to modulate the NMDA receptor can beevaluated by procedures known in the art and/or described herein.

In certain embodiments, the present disclosure provides a method oftreating and or ameliorating a disease and/or disorder of the nervoussystem in a patient in need thereof by administering an effective amountof a disclosed compound. Exemplary diseases and disorders of the nervoussystem include psychiatric diseases, neurological diseases, andneurodevelopmental disorders, further described below.

In one embodiment, an exemplary psychiatric disease is schizophrenia.Schizophrenia is a debilitating mental disorder encompassing threesymptom domains: positive (psychosis, hallucination, delusions),negative (withdrawal), and cognitive (global reduction in cognitiveability). Positive symptoms of Schizophrenia typically emerge early inadulthood and are treated with antipsychotic medications. However,cognitive deficits are severe, emerge in the adolescent prodromal stage,are resistant to antipsychotic therapy, and are the leading cause oflifetime disability as measured by impaired global function (inabilityto live independently, unemployment, etc). NMDA receptor hypofunction isthe leading hypothesis for the cause of schizophrenia. This hypothesisis supported by substantial clinical evidence including clinicalpharmacology, electrophysiology, imaging, cognition, computationalneuroscience, neuroanatomical studies, and genetics. In particular,several lines of evidence implicate hypofunction of GluN2B-containingNMDA receptors in schizophrenia.

The present disclosure provides herein a method of treatingschizophrenia, including positive, negative, and cognitive symptoms, ina patient in need thereof, comprising administering an effective amountof a disclosed compound. For example, provided herein are methods ofameloiorating positive, negative, and cognitive symptoms of a patientnot adequately treated by approved antipsychotic medications, forexample the treatment of cognitive impairments in schizophrenia, byadministering an effective amount of a disclosed compound to such apatient.

Also provided herein are methods to improve cognitive and globalfunction, and/or substantially preventing the onset of schizophrenia inpeople at risk of developing schizophrenia, by administering aneffective amount of a disclosed compound to such a patient.

Contemplated herein are methods of treating and/or amelioratingcognitive and emotional deficits and other symptoms associated withexemplary psychiatric disorders including major depressive disorder, andincluding but not limited to those suffering from bipolar disorder,obsessive-compulsive disorder, dysphobic disorder, dysthymic disorder,psychotic depression, post-traumatic stress disorder, and other anxietydisorders. For example, provided herein are methods of treatingattention deficit disorder, ADHD (attention deficit hyperactivitydisorder), schizophrenia, anxiety, amelioration of opiate, nicotineand/or ethanol addiction (e.g., method of treating such addiction orameliorating the side effects of withdrawing from such addiction),spinal cord injury, diabetic retinopathy, traumatic brain injury, and/orpost-traumatic stress syndrome in a patient in need thereof, thatincludes administering a disclosed compound.

In other embodiments, provided herein is a method of treating and/orameliorating cognitive and emotional deficits and other symptomsresulting from neurological diseases, including but not limited to apatient suffering from Alzheimer's disease, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis,and seizure disorders comprising administering to the patient aneffective amount of a disclosed compound.

The present disclosure contemplates a method of treating and/orameliorating dysfunction caused by neurodevelopmental disorders, e.g.,abnormal brain development, including but not limited to Rett Syndrome,Attention Deficit and Hyperactivity Disorder, autism and autism spectrumdisorders such as Phelan-McDermid Syndrome, and other forms ofintellectual disability such as Fragile X syndrome, tuberous sclerosis,Smith-Lemli-Opitz Syndrome, and Down's syndrome. A method is alsoprovided to treat patients suffering from abnormal brain functionresulting from infections of the central nervous system, exposure totoxic agents or other xenobiotics or naturally occurring toxins, and/orautoimmune disorders including, but not limited to anti-NMDA receptorencephalitis comprising administering an effective amount of a disclosedcompound.

In particular, in certain embodiments, the disclosure provides a methodof treating, preventing, and/or preventing the development of the abovemedical indications comprising administering to a subject in needthereof a therapeutically effective amount of a compound describedherein, such as a compound of Formula.

In certain embodiments, the compound utilized by one or more of theforegoing methods is one of the generic, subgeneric, or specificcompounds described herein, such as a compound of Formula I.

Disclosed compounds may be administered to patients in need of suchtreatment in dosages that will provide optimal pharmaceutical efficacy.It will be appreciated that the dose required for use in any particularapplication will vary from patient to patient, not only with theparticular compound or composition selected, but also with the route ofadministration, the nature of the condition being treated, the age andcondition of the patient, concurrent medication or special diets thenbeing followed by the patient, and other factors which those skilled inthe art will recognize, with the appropriate dosage ultimately being atthe discretion of the attendant physician. For treating clinicalconditions and diseases noted above, a compound of this invention may beadministered orally, subcutaneously, topically, parenterally, byinhalation spray or rectally in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. Parenteral administration may include subcutaneousinjections, intravenous or intramuscular injections or infusiontechniques.

Treatment can be continued for as long or as short a period as desired.The compositions may be administered on a regimen of, for example, oneto four or more times per day. A suitable treatment period can be, forexample, at least about one week, at least about two weeks, at leastabout one month, at least about six months, at least about 1 year, orindefinitely. A treatment regimen can include a corrective phase, duringwhich dose sufficient to maintain cognitive and/or emotional function isadministered, and can be followed by a maintenance phase, during which ae.g. a lower dose sufficient to prevent a deficit in cognitive and/oremotional function is administered. A suitable maintenance dose islikely to be found in the lower parts of the dose ranges providedherein, but corrective and maintenance doses can readily be establishedfor individual subjects by those of skill in the art without undueexperimentation, based on the disclosure herein.

III. Pharmaceutical Compositions and Kits

Another aspect of the invention provides pharmaceutical compositionscomprising compounds as disclosed herein formulated together with apharmaceutically acceptable carrier. In particular, the presentdisclosure provides pharmaceutical compositions comprising compounds asdisclosed herein formulated together with one or more pharmaceuticallyacceptable carriers. These formulations include those suitable for oral,rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular,intradermal, or intravenous) rectal, vaginal, or aerosol administration,although the most suitable form of administration in any given case willdepend on the degree and severity of the condition being treated and onthe nature of the particular compound being used. For example, disclosedcompositions may be formulated as a unit dose, and/or may be formulatedfor oral or subcutaneous administration.

Exemplary pharmaceutical compositions of this invention may be used inthe form of a pharmaceutical preparation, for example, in solid,semisolid or liquid form, which contains one or more of the compound ofthe invention, as an active ingredient, in admixture with an organic orinorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The active objectcompound is included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or conditionof the disease.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical carrier, e.g.,conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, lactose, sucrose, glucose,mannitol, and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, acetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.In the case of capsules, tablets and pills, the compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the subject compositionmoistened with an inert liquid diluent. Tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, may optionally bescored or prepared with coatings and shells, such as enteric coatingsand other coatings well known in the pharmaceutical-formulating art.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the subject composition, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, cyclodextrins and mixtures thereof.

Suspensions, in addition to the subject composition, may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating excipients or carriers comprising,for example, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the body cavity and release theactive agent.

Dosage forms for transdermal administration of a subject compositioninclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. The active component may be mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to asubject composition, excipients, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays may contain, in addition to a subject composition,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays may additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Compositions and compounds of the present invention may alternatively beadministered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. A non-aqueous (e.g., fluorocarbon propellant) suspension couldbe used. Sonic nebulizers may be used because they minimize exposing theagent to shear, which may result in degradation of the compoundscontained in the subject compositions. Ordinarily, an aqueous aerosol ismade by formulating an aqueous solution or suspension of a subjectcomposition together with conventional pharmaceutically acceptablecarriers and stabilizers. The carriers and stabilizers vary with therequirements of the particular subject composition, but typicallyinclude non-ionic surfactants (Tweens, Pluronics, or polyethyleneglycol), innocuous proteins like serum albumin, sorbitan esters, oleicacid, lecithin, amino acids such as glycine, buffers, salts, sugars orsugar alcohols. Aerosols generally are prepared from isotonic solutions.

Pharmaceutical compositions of the present disclosure suitable forparenteral administration comprise a subject composition in combinationwith one or more pharmaceutically-acceptable sterile isotonic aqueous ornon-aqueous solutions, dispersions, suspensions or emulsions, or sterilepowders which may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate and cyclodextrins. Proper fluidity may be maintained,for example, by the use of coating materials, such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants

In another aspect, the invention provides enteral pharmaceuticalformulations including a disclosed compound and an enteric material; anda pharmaceutically acceptable carrier or excipient thereof. Entericmaterials refer to polymers that are substantially insoluble in theacidic environment of the stomach, and that are predominantly soluble inintestinal fluids at specific pHs. The small intestine is the part ofthe gastrointestinal tract (gut) between the stomach and the largeintestine, and includes the duodenum, jejunum, and ileum. The pH of theduodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH ofthe distal ileum is about 7.5. Accordingly, enteric materials are notsoluble, for example, until a pH of about 5.0, of about 5.2, of about5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary entericmaterials include cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP),hydroxypropyl methylcellulose acetate succinate (HPMCAS), celluloseacetate trimellitate, hydroxypropyl methylcellulose succinate, celluloseacetate succinate, cellulose acetate hexahydrophthalate, cellulosepropionate phthalate, cellulose acetate maleate, cellulose acetatebutyrate, cellulose acetate propionate, copolymer of methylmethacrylicacid and methyl methacrylate, copolymer of methyl acrylate,methylmethacrylate and methacrylic acid, copolymer of methylvinyl etherand maleic anhydride (Gantrez ES series), ethylmethyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylatecopolymer, natural resins such as zein, shellac and copal collophorium,and several commercially available enteric dispersion systems (e.g.,Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S 100,Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubilityof each of the above materials is either known or is readilydeterminable in vitro. The foregoing is a list of possible materials,but one of skill in the art with the benefit of the disclosure wouldrecognize that it is not comprehensive and that there are other entericmaterials that would meet the objectives of the present invention.

Pharmaceutical compositions of the present disclosure may also beadministered by the use of monoclonal antibodies as individual carriersto which the disclosed compounds are coupled. The disclosed compoundscan also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, Disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Advantageously, the invention also provides kits for use by a e.g. aconsumer in need of a disclosed NMDA modulator. Such kits include asuitable dosage form such as those described above and instructionsdescribing the method of using such dosage form to mediate, reduce orprevent inflammation. The instructions would direct the consumer ormedical personnel to administer the dosage form according toadministration modes known to those skilled in the art. Such kits couldadvantageously be packaged and sold in single or multiple kit units. Anexample of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of a first compound can consistof one tablet or capsule while a daily dose of the second compound canconsist of several tablets or capsules and vice versa. The memory aidshould reflect this.

EXAMPLES

The compounds described herein can be prepared in a number of ways basedon the teachings contained herein and synthetic procedures known in theart. In the description of the synthetic methods described below, it isto be understood that all proposed reaction conditions, including choiceof solvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, can be chosen to be the conditionsstandard for that reaction, unless otherwise indicated. It is understoodby one skilled in the art of organic synthesis that the functionalitypresent on various portions of the molecule should be compatible withthe reagents and reactions proposed. Substituents not compatible withthe reaction conditions will be apparent to one skilled in the art, andalternate methods are therefore indicated. The starting materials forthe examples are either commercially available or are readily preparedby standard methods from known materials.

At least some of the compounds identified as “Intermediates” herein arecontemplated as compounds of the invention.

¹H NMR spectral chemical shifts are expressed in ppm relative totetramethylsilane. The following abbreviations have been used: br=broadsignal, s=singlet, d=doublet, dd=double doublet, ddd=double doubledoublet, dt=double triplet, t=triplet, td=triple doublet, q=quartet,m=multiplet.

Example 1: Preparation3-[2-(azetidin-1-yl)-2-oxoethyl]-5-(4-chlorophenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one

Step 1: Ethyl 2-amino-4-(4-chlorophenyl)thiophene-3-carboxylate

To a stirred solution of 1-(4-chlorophenyl)ethanone (30.0 g, 194.04mmol) in ethanol (250 mL) was added ethyl 2-cyanoacetate (30.98 mL, 291mmol), sulfur powder (8.09 g, 252.0 mml) and morpholine (33.47 mL, 388mmol). The reaction mixture was refluxed for 18 h and was concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography using 10% ethyl acetate in hexane to afford ethyl2-amino-4-(4-chlorophenyl)thiophene-3-carboxylate as a off-white solid(10.65 g, 19.5% yield).

Calculated (M+H): 282.03, Found (M+H): 282.1.

Step 2: 5-(4-chlorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one

A mixture of ethyl 2-amino-4-(4-chlorophenyl)thiophene-3-carboxylate(10.6 g, 37.62 mmol) and formamide was heated at 190° C. for 16 h. Thereaction mixture was cooled to room temperature and poured on to crushedice and stirred for 30 minutes. The precipitated product was filtered,washed with water, dried to afford the title compound5-(4-chlorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one as a dark brown solid(7.74 g, 78.2% yield).

Calculated (M+H): 263.0; Found (M+H): 263.0.

Step 3: Ethyl2-(5-(4-chlorophenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate

To a solution of 5-(4-chlorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one(7.72 g, 29.39 mmol) in acetone (250 mL) was added potassium carbonate(12.19 g, 88.17 mmol) and ethyl-2-bromoacetate (6.52 mL, 58.77 mmol).The reaction mixture was heated at 55° C. for 16 h. After completion ofthe reaction, the reaction mixture was cooled to room temperature andfiltered. The filtrate was concentrated under reduced pressure to affordcrude product, which was purified by silica gel column chromatographyusing 10% ethyl acetate in hexane to afford ethyl2-(5-(4-chlorophenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate(10.51 g, crude) as a off-white solid.

Calculated (M+H): 349.03; Found (M+H): 349.0.

Step 4:2-(5-(4-chlorophenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetic Acid

To a solution of ethyl2-(5-(4-chlorophenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate (10.5g, 30.1 mmol) in tetrahydrofuran:water mixture (100 mL, 1:1) was addedlithium hydroxide monohydrate (6.31 g, 150.52 mmol) at room temperatureand stirred at the same temperature for 1 h. After completion of thereaction, the reaction mixture was concentrated, the residue was dilutedwith water (50 mL) and acidified with 1.5N hydrochloric acid to pH 2 to3. The precipitated product was filtered, washed with water and dried toafford 2-(5-(4-chlorophenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)aceticacid (9.1 g, 94.2% yield).

Calculated (M+H): 321.0; Found (M+H): 321.0.

Step 5:3-[2-(azetidin-1-yl)-2-oxoethyl]-5-(4-chlorophenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one

To a stirred suspension of2-(5-(4-chlorophenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetic acid(0.1 g, 0.31 mmol) in dichloromethane (10 mL) and N,N-dimethyl formamide(1 mL) mixture, were added triethylamine (0.13 mL, 0.93 mmol) andazetidine hydrochloride (0.035 g, 0.37 mmol) at room temperature. Thereaction mixture was cooled to 0° C., 1-propylphosphonic anhydride (T3P)(0.36 mL, 0.62 mmol, 50% solution in ethyl acetate) was added andstirred at room temperature for 24 h. The reaction mixture was dilutedwith water (50 mL) and extracted with dichloromethane (2×50 mL). Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand concentrated. The crude product was purified by silica gel columnchromatography using 4% methanol in dichloromethane to afford3-(2-(azetidin-1-yl)-2-oxoethyl)-5-(4-chlorophenyl)thieno[2,3-d]pyrimidin-4(3H)-oneas a off-white solid (0.015 g, 13.4% yield).

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34 (s, 1H), 7.59 (s, 1H), 7.50 (d,J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 4.59 (s, 2H), 4.23 (t, J=7.6 Hz,2H), 3.87 (t, J=7.6 Hz, 2H), 2.31-2.22 (m, 2H).

Calculated (M+H): 360.05, Found (M+H): 360.1.

HPLC purity: 98.7%.

Examples 2-15

The following compounds were prepared by the method described above:

Ex. No. Structure Analytical data  2

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.35 (s, 1H), 7.61 (s, 1H), 7.5 (d, J= 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.78-4.73 (m, 4H), 4.35 (t, J =12 Hz, 2H). Calculated (M + H): 396.03, Found (M + H): 396.0, HPLCpurity: 99.73%  3

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.32 (s, 1H), 7.59 (s, 1H), 7.49 (d,J = 8.4 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 4.70-4.65 (m, 4H), 4.59 (s,2H), 4.02 (s, 2H), 4.06 (s, 2H). Calculated (M + H): 402.06, Found (M +H): 402.1, HPLC Purity: 98.57%  4

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.35 (s, 1H), 7.60 (s, 1H), 7.50 (d,J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.63 (s, 2H), 4.42-4.38 (m,1H), 4.25 (brs, 1H), 4.07-4.04 (m, 2H), 3.69-3.67 (m, 1H), 3.21 (s, 3H).Calculated (M + H): 390.06, Found (M + H): 390.1, HPLC purity: 99.27%  5

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.37 (s, 1H), 7.75-7.69 (m, 5H), 4.74(brs, 4H), 4.35 (t, J = 12 Hz, 2H). Calculated (M + H): 430.06, Found(M + H): 430.1, HPLC purity: 99.47%  6

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.35 (s, 1H), 7.95 (brs, 1H), 7.77(d, J = 3.6 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 4.77- 4.71 (m, 4H), 4.33(t, J = 12.0 Hz, 2H). Calculated (M + H): 464.02; Found (M + H): 464.3,HPLC purity: 99.84%  7

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34 (s, 1H), 7.57 (s, 1H), 7.53-7.50(m, 2H), 7.20 (t, J = 8.8 Hz, 2H), 4.77-4.73 (m, 4H), 4.35 (t, J = 2.4Hz, 2H). Calculated (M + H): 380.06; Found M + H: (380.1), HPLC purity:99.72%  8

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.33 (s, 1H), 7.49 (s, 1H), 7.37 (d,J = 8 Hz, 2H), 7.17 (d, J = 7.2 Hz, 2H), 4.77-4.72 (m, 4H), 4.35 (t, J =12.4 Hz, 2H), 2.33 (s, 3H). Calculated (M + H): 376.09, Found (M + H):376.1. HPLC purity: 99.27%  9

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.34 (s, 1H), 7.69 (dd, J = 2 Hz, 7.6Hz, 1H), 7.67 (s, 1H), 7.50-7.47 (m, 1H), 7.44-7.39 (m, 1H), 4.77-4.72(m, 4H), 4.34 (t, J = 12.4 Hz, 2H). Calculated (M + H): 414.02, Found(M + H): 414.0. HPLC purity: 99.07% 10

¹H NMR (400 MHz, DMSO-d6) δ (ppm); 8.34 (s, 1H), 7.75 (d, J = 1.2 Hz,1H), 7.71 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.48-7.46 (m, 1H),4.88-4.71 (m, 4H), 4.53- 4.39 (m, 2H), 4.14-3.98 (m, 2H). Calculated(M + H): 444.01; Found (M + 1): 444.0. HPLC purity 99.55% 11

¹H NMR (400 MHz, DMSO-d6) δ (ppm); 8.35 (s, 1H), 7.74 (s, 1H), 7.71 (s,1H), 7.63 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 4.68 (s, 2H),4.42-4.29 (m, 2H), 4.03-3.95 (m, 2H), 1.58 (d, J = 22 Hz, 3H).Calculated (M + H): 426.02; Found (M + 1): 426.0. HPLC purity 99.8% 12

¹H NMR (400 MHz, DMSO-d6) δ (ppm); 8.34 (s, 1H), 7.70-7.64 (m, 2H),7.50-7.47 (m, 1H), 7.43- 7.39 (m, 1H), 4.69 (s, 2H), 4.40- 4.28 (m, 2H),4.03-3.89 (m, 2H), 1.93-1.81 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).Calculated (M + H): 424.06; Found (M + 1): 424.3. HPLC purity 99.04% 13

¹H NMR (400 MHz, DMSO-d6) δ (ppm); 8.34 (s, 1H), 7.70-7.67 (m, 2H),7.50-7.47 (m, 1H), 7.44- 7.39 (m, 1H), 4.88-4.70 (m, 4H), 4.50-4.41 (m,2H), 4.11-4.06 (m, 2H). Calculated (M + H): 428.04; Found (M + 1):428.1. HPLC purity 99.66% 14

¹H NMR (400 MHz, DMSO-d6) δ (ppm); 8.34 (s, 1H), 7.70-7.66 (m, 2H),7.50-7.47 (m, 1H), 7.44- 7.39 (m, 1H), 4.68 (s, 2H), 4.42- 4.29 (m, 2H),4.03-3.95 (m, 2H), 1.58 (d, J = 21.6 Hz, 3H). Calculated (M + H):410.05; Found (M + 1): 410.1. HPLC purity 99.91% 15

¹H NMR (400 MHz, DMSO-d6) δ (ppm); 8.35 (s, 1H), 7.74 (s, 1H), 7.71 (s,1H), 7.63 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.69 (s, 2H),4.37-4.28 (m, 2H), 4.03-3.89 (m, 2H), 1.91- 1.83 (m, 2H), 0.91 (t, J =7.2 Hz, 3H). Calculated (M + H): 440.03; Found (M + 1): 440. HPLC purity99.5%

Example 16:3-[2-(azetidin-1-yl)-2-oxoethyl]-6-(4-chlorophenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one

Step 1: 6-bromothieno[2,3-d]pyrimidin-4(3H)-one

To a stirred solution of thieno[2,3-d]pyrimidin-4(3H)-one (4.0 g, 12.33mmol) and potassium acetate (17.25 g, 210.32 mmol) in acetic acid (100mL) was added slowly bromine (2.7 mL, 52.57 mmol) at 0° C. The reactionmixture was stirred at room temperature for 24 h. After completion ofthe reaction, the reaction mixture was concentrated, the residue wasbasified with saturated sodium bicarbonate solution and extracted withethyl acetate (2×1000 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated to afford the titlecompound 6-bromothieno[2,3-d]pyrimidin-4(3H)-one (3.4 g crude, 56%yield) as brown solid.

Calculated (M+H): 230.91; Found (M+H): 231.0.

Step 2: Ethyl 2-(6-bromo-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate

To a stirred suspension of 6-bromothieno[2,3-d]pyrimidin-4(3H)-one (2.0g, 8.66 mmol) and potassium carbonate (3.6 g, 25.98 mmol) in acetone,was added ethyl 2-bromoacetate (1.92 mL, 17.31 mmol) at room temperatureand resulting mixture was heated at 55° C. for 1 h. The reaction mixturewas cooled to room temperature, filtered and the filtrate was evaporatedto afford the crude product. The crude product was purified by silicagel column chromatography using 50% ethyl acetate in hexane to affordthe title compound ethyl2-(6-bromo-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate (1.91 g, 69.7%yield) as off-white solid.

Calculated (M+H): 316.95; Found (M+H): 317.2.

Step 3:2-(6-(4-chlorophenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetic Acid

To a stirred suspension of ethyl2-(6-bromo-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate (0.1 g, 0.31mmol) and (4-chlorophenyl)boronic acid (0.12 g, 0.79 mmol) in1,4-dioxane:water mixture (10 mL, 1:1) was added potassium carbonate(0.13 g, 0.94 mmol). The resulting mixture was purged with argon for 10minutes. Then tetrakis(triphenylphosphine) palladium(0) (0.02 g, 0.01mmol) was added and the reaction mixture was heated at 110° C. for 3 h.After completion of the reaction, the reaction mixture was cooled toroom temperature and filtered through the celite bed. The filtrate wasdiluted water (20 mL) and acidified with 1.5 N hydrochloric acidsolution at 0° C. The precipitated solid was filtered and dried undersuction to afford the title compound2-(6-(4-chlorophenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetic acid(0.09 g, 90% yield) as white solid.

Calculated (M+H): 321.0; Found (M+H): 321.0.

Step 4:3-[2-(azetidin-1-yl)-2-oxoethyl]-6-(4-chlorophenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one

To a stirred suspension of2-(6-(4-chlorophenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetic acid(0.1 g, 0.31 mmol) in dichloromethane (20 mL) and N,N-dimethyl formamide(1 mL) mixture, were added triethylamine (0.26 mL, 1.87 mmol) andazetidine hydrochloride (0.035 g, 0.37 mmol) at room temperature. Thereaction mixture was cooled to 0° C., 1-propylphosphonic anhydride (T3P)(0.36 mL, 0.62 mmol, 50% solution in ethyl acetate) was added andstirred at room temperature for 16 h. The reaction mixture was dilutedwith water (50 mL) and extracted with dichloromethane (2×50 mL). Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand concentrated. The crude product was purified by silica gel columnchromatography using 5% methanol in dichloromethane to afford3-(2-(azetidin-1-yl)-2-oxoethyl)-6-(4-chlorophenyl)thieno[2,3-d]pyrimidin-4(3H)-oneas a off-white solid (0.024 g, 21.4% yield).

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31 (s, 1H), 7.84 (s, 1H), 7.80 (d,J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 4.65 (s, 2H), 4.28 (t, J=7.6 Hz,2H), 3.91 (t, J=7.6 Hz, 2H), 2.33-2.25 (m, 2H)

Calculated (M+H): 360.05, Found (M+H): 360.0.

HPLC purity: 97.02%.

Example 17

The following compound was prepared by the method described above:

Ex. No. Structure Analytical data 17

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.32 (s, 1H), 7.85 (s, 1H), 7.80 (d,J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.69 (s, 2H), 4.48-4.44 (m,1H), 4.28-4.27 (m, 1H), 4.13-4.07 (m, 2H), 3.73-3.70 (m, 1H), 3.24 (s,3H); Calculated (M + H): 390.06, Found (M + H): 390.1. HPLC purity:95.82%

Example 18:5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-6-methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one

Step 1: ethyl 2-amino-5-methylthiophene-3-carboxylate

To a solution of propionaldehyde (5.0 g, 44.16 mmol) and ethyl2-cyanoacetate (6.33 g, 88.33 mmol) in ethanol (200 mL) was addedpiperazine (19.01 g, 52.99 mmol) followed by S₈ (1.69 g, 52.99 mmol).The reaction mixture was heated at 85° C. for 16 h. After completion ofthe reaction, the reaction mixture was diluted with water (200 mL) andextracted with ethyl acetate (3×200 mL). The combined organic layer wasdried over anhydrous sodium sulphate, filtered and concentrated to getthe crude product which was purified by silica gel column chromatographyusing 10% ethyl acetate in hexane to afford the title compound ethyl2-amino-5-methylthiophene-3-carboxylate (2.3 g, 28% yield) as yellowoily liquid.

Calculated (M+H): 186.05; Found (M+H): 186.

Step 2: 6-methylthieno [2,3-d]pyrimidin-4(3H)-one

A suspension of ethyl 2-amino-5-methylthiophene-3-carboxylate (2.3 g,0.43 mmol) and form amide (28 mL) was heated at 180° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was quenched with water(100 mL) and stirred for 30 minutes. The precipitated solid was filteredand washed with pentane and dried under suction to get the titlecompound 6-methylthieno[2,3-d]pyrimidin-4(3H)-one (1.0 g, crude) as offwhite solid.

Calculated (M+H): 167.02; Found (M+H): 167.1.

Step 3: 5-bromo-6-methylthieno [2,3-d]pyrimidin-4(3H)-one

To a solution of 6-methylthieno [2,3-d]pyrimidin-4(3H)-one (1.0 g, 6.02mmol) in acetic acid (20 mL) was added bromine (0.46 mL, 18.05 mmol)drop-wise at room temperature. The reaction mixture was stirred at thesame temperature for 16 h. After completion of the reaction, thereaction mixture was concentrated, the residue was diluted withsaturated sodium bicarbonate solution and extracted with ethyl acetate(3×100 mL). The combined organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated to get crude product which waspurified by silica gel column chromatography using 8% methanol indichloromethane to afford the title compound 5-bromo-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (0.54 g, 36.7% yield) as off white solid.

Calculated (M+H): 244.93; Found (M+H): 245.1.

Step 4: Ethyl 2-(5-bromo-6-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate

To a solution of 5-bromo-6-methylthieno [2,3-d]pyrimidin-4(3H)-one (0.54g, 2.20 mmol) in acetone (20 mL), ethyl bromoacetate (0.8 mL, 4.40 mmol)was added followed by potassium carbonate (0.91 g, 6.6 mmol). Thereaction mixture was heated at 55° C. for 2 h. After completion of thereaction, the reaction mixture was filtered and the filtrate wasconcentrated. The crude product was purified by silica gel columnchromatography using 15% ethyl acetate in hexane to afford the titlecompound ethyl2-(5-bromo-6-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate (0.4 g,54% yield) as off-white solid.

Calculated (M+H): 330.97; Found (M+H): 331.2.

Step 5:2-(5-(4-chlorophenyl)-6-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)aceticAcid

To a solution of ethyl2-(5-bromo-6-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate (0.1 g,0.30 mmol) in 1,4-dioxane:water mixture (10 mL, 4:1),4-chlorophenyl)boronic acid (0.06 g, 0.39 mmol), sodium carbonate (0.1g, 0.96 mmol) were added and the reaction mixture was purged the mixturewith argon for 30 minutes. Then bis(triphenylphosphine)palladium(II)dichloride (0.02 g, 0.03 mmol) was added and the reaction mixture wasstirred at 100° C. for 16 h. After completion of the reaction, thereaction mixture was diluted with water (50 mL), extracted with ethylacetate (2×50 mL) and the organic layer was discarded. The aqueous layerpH was adjusted to acidic by the addition of 1.5N hydrochloric acidsolution and extracted with ethyl acetate (3×50 mL). The combinedorganic layer was dried over anhydrous sodium sulphate, filtered andconcentrated to get crude product which was purified by silica gelcolumn chromatography using 30% ethyl acetate in hexane to afford thetitle compound ethyl2-(5-(4-chlorophenyl)-6-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)aceticacid (0.06 g, 59.4% yield) as off-white solid.

Calculated (M+H): 335.02; Found (M+H): 335.2.

Step 6:5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-6-methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one

To a stirred solution of2-(5-(4-chlorophenyl)-6-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)aceticacid (0.08 g, 0.23 mmol) in dichloromethane (15 mL), triethylamine (0.1mL, 0.71 mmol) was added at room temperature. The reaction mixture wascooled to 0° C., 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.068g, 0.35 mmol) and hydroxybenzotriazole (0.039 g, 0.28 mmol) were addedand stirred for 30 mins. 3,3-difluoroazetidine hydrochloride (0.046 g,0.35 mmol) was added at 0° C. and the reaction mixture was stirred atroom temperature for 16 h. After completion of the reaction, thereaction mixture was diluted with water (20 mL) and extracted withdichloromethane (2×50 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated to get crudecompound which was purified by column chromatography followed bypreparative HPLC (analytical conditions: column: Inertsil ODS 3V (250mm×4.6 mm×5μ), mobile phase (A): 0.01% ammonia in water, mobile phase(B): acetonitrile, flow rate: 1.0 mL/min, T/% B: 0/10, 10/70, 25/70,27/10, 30/10) to get the title compound5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-6-methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one(0.02 g, 20.4% yield) as white solid.

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.26 (s, 1H), 7.42 (d, J=8.4 Hz, 2H),7.27 (d, J=8.4 Hz, 2H), 4.72-4.65 (m, 4H), 4.32 (t, J=12.4 Hz, 2H),2.307 (s, 3H).

Calculated (M+H): 410.84; Found (M+H): 410.1.

HPLC purity: 98.93%.

Example 19:5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2-methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one

Step 1: Ethyl 2-amino-4-(4-chlorophenyl)thiophene-3-carboxylate

To a stirred solution of 1-(4-chlorophenyl)ethanone (10.0 g, 64.93 mmol)in ethanol (200 mL) were added ethyl 2-cyanoacetate (16.0 ml, 129.87mmol), morpholine (20 mL, 227.27 mmol), and sulfur (4.0 g, 97.40 mmol)at room temperature and the RM was stirred at 100° C. for 44 h. Aftercompletion of the reaction, the RM was concentrated to get the crudeproduct which was purified by silica gel column chromatography using 10%ethyl acetate in hexane to afford the title compound ethyl2-amino-4-(4-chlorophenyl)thiophene-3-carboxylate (3.9 g, 21.0% yield)as off white solid.

Calculated (M+H): 282.03; Found (M+H): 282.2.

Step 2: 5-(4-chlorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one

To a stirred solution of ethyl2-amino-4-(4-chlorophenyl)thiophene-3-carboxylate (1.0 g, 3.55 mmol) inacetonitrile (8 mL), was added 4N hydrochloric acid in dioxane (18 mL)at room temperature and the RM was stirred at 100° C. for 12 h in asealed tube. After completion of the reaction, the reaction mixture wascooled to room temperature and diluted with water (100 mL). Theprecipitated solid was filtered, washed with water (50 mL) and driedunder suction to afford the title compound5-(4-chlorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (0.8 g, 88%yield) as off white solid.

Calculated (M+H): 277.01; Found (M+H): 277.0.

Step 3: Ethyl2-(5-(4-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate

To a stirred solution of5-(4-chlorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (0.4 g, 1.44mmol) in acetone (20 mL), potassium carbonate (0.6 g, 4.33 mmol) andethylbromoacetate (0.48 g, 2.88 mmol) were added at room temperature andthe reaction mixture was heated at 60° C. for 6 h. The reaction mixturewas filtered and the filtrate was concentrated to get the crude compoundwhich was purified by silica gel column chromatography using 30% ethylacetate in hexane to get the title compound ethyl2-(5-(4-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate(0.38 g, 57.0% yield) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.52 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H),4.86 (s, 2H), 4.16-4.10 (m, 2H), 2.56 (s, 3H), 1.23-1.16 (m, 3H).

Calculated (M+H): 363.05; Found (M+H): 363.1.

HPLC purity: 99.86%.

Step 4:2-(5-(4-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)aceticAcid

To a stirred solution of ethyl2-(5-(4-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetate(0.38 g, 1.04 mmol) in tetrahydrofuran:water mixture (20 mL, 4:1),lithium hydroxide monohydrate (0.21 g, 5.23 mmol) was added and thereaction mixture was stirred at room temperature for 1 h. Aftercompletion of the reaction, the reaction mixture was evaporated andacidified with 1.5N hydrochloric acid solution. The precipitated solidwas filtered, washed with water and dried under suction to get the titlecompound2-(5-(4-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)aceticacid (0.22 g, 62.0% yield) as off white solid.

Calculated (M+H): 335.02; Found (M+H): 335.0.

Step 5:5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2-methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one

To a stirred solution of2-(5-(4-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)aceticacid (0.11 g, 0.32 mmol) in dichloromethane (10 mL) were addedtriethylamine (0.27 mL, 1.91 mmol) and 3,3-difluoroazetidine (0.04 g,0.39 mmol) at room temperature and the reaction mixture was stirred for10 minutes. Then 1-propanephosphonic anhydride (T₃P) (0.15 mL, 0.49mmol, 50% solution in ethyl acetate) was added at 0° C. and the reactionmixture was stirred at room temperature for 12 h. After completion ofthe reaction, the reaction mixture was diluted with water (20 mL) andextracted with dichloromethane (3×50 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated to getthe crude compound which was purified by silica gel columnchromatography using 20% ethyl acetate in hexane to afford the titlecompound5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2-methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one(0.045 g, 34% yield) as off white solid.

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 7.5-7.47 (m, 3H), 7.41 (d, J=8.8 Hz,2H), 4.82 (s, 2H), 4.77 (t, J=12.8 Hz, 2H), 4.34 (t, J=12.4 Hz, 2H),2.48 (s, 3H).

Calculated (M+H): 410.05; Found M+H: 410.1.

HPLC: 99.98%.

Example 20:5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[3-(3,3-difluoroazetidin-1-yl)-3-oxopropyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one

Step 1:5-(4-chloro-3-(trifluoromethyl)phenyl)thieno[2,3-d]pyrimidin-4(3H)-one

A mixture of ethyl2-amino-4-(4-chloro-3-(trifluoromethyl)phenyl)thiophene-3-carboxylate(3.0 g, 8.58 mmol) and formamide (30 mL) was heated at 180° C. for 16 h.The mixture was allowed to cool to room temperature and diluted withwater (150 mL). The precipitated compound was filtered, washed withwater and dried under vacuum to afford the title compound5-(4-chloro-3-(trifluoromethyl)phenyl)thieno[2,3-d]pyrimidin-4(3H)-one(3.2 g, crude) as a brown solid, which was taken for next step withoutfurther purification.

Calculated (M+H): 330.98, Found (M+H): 330.0.

Step 2: Ethyl3-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate

To a mixture of5-(4-chloro-3-(trifluoromethyl)phenyl)thieno[2,3-d]pyrimidin-4(3H)-one(0.4 g, 1.21 mmol) and potassium carbonate (0.5 g, 3.63 mmol) in dryacetone (50 mL) was added ethyl 2-bromoacetate (0.3 g, 2.42 mmol). Theresulting mixture was heated at 55° C. for 3 h. The reaction mixture wasallowed to cool to room temperature, filtered and the filtrate wasconcentrated under vacuum to afford crude product, which was purified bysilica gel column chromatography using 35% ethyl acetate in hexane toafford the title compound ethyl3-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (0.36 g, 69% yield) as white solid.

Calculated (M+H): 431.04, Found (M+1): 431.0.

Step 3:3-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanoicAcid

To a suspension of ethyl3-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate(0.36 g, 0.84 mmol) in tetrahydrofuran:water mixture (20 mL, 1:1) wasadded lithium hydroxide monohydrate (0.1 g, 2.51 mmol) at 0° C. Theresulting suspension was gradually allowed to warm to room temperatureand stirred for 3 h. The reaction mixture was allowed to cool to 0° C.and acidified with 1.5M hydrochloric acid solution to pH 2 to 3. Theprecipitated product was filtered, washed with water, dried to obtainthe title compound3-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanoicacid (0.3 g, 91% yield) as a colorless solid.

Calculated (M+H): 403.0, Found (M+H): 403.0.

Step 4:5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[3-(3,3-difluoroazetidin-1-yl)-3-oxopropyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one

To a solution of3-(5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanoicacid (0.07 g, 0.17 mmol) in dichloromethane (20 mL) were added3,3-difluoroazetidine hydrochloride (0.027 g, 0.20 mmol) andtriethylamine (0.2 mL, 1.39 mmol). The reaction mixture was cooled to 0°C. and 1-propanephosphonic anhydride (T₃P) (0.22 mL, 0.34 mmol, 50%solution in ethyl acetate) was added drop-wise. The reaction mixture wasallowed to warm to room temperature and stirred for 6 h. The mixture wasdiluted with dichloromethane (25 mL), washed with water (2×50 mL), brine(30 mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to afford crude product, which was purified bysilica gel column chromatography using 5% methanol in dichloromethane aseluent to afford the title compound5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[3-(3,3-difluoroazetidin-1-yl)-3-oxopropyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one(0.032 g, 38.5% yield) as white solid.

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.45 (s, 1H), 7.98 (s, 1H), 7.81 (d,J=8.0 Hz, 1H), 7.73-7.72 (m, 2H), 4.50 (t, J=12 Hz, 2H), 4.21 (t, J=12.4Hz, 2H), 4.14 (brs, 2H), 2.63 (brs, 2H).

Calculated (M+H): 478.03, Found (M+H): 478.0.

HPLC purity: 98.37%.

Example 21:5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2-(trifluoromethyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one

Step 1:5-(4-chlorophenyl)-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-4(3H)-one

To a stirred solution of ethyl2-amino-4-(4-chlorophenyl)thiophene-3-carboxylate (1.0 g, 3.55 mol) inethanol (10 mL), was added 2,2,2-trifluoroacetimidamide (3.97 g, 35.49mol). The resulting mixture was heated under microwave irradiation at100° C. for 1 h. The progress of the reaction was monitored by TLC,since TLC showed presence of starting material, again 5 eq of2,2,2-trifluoroacetimidamide was added and the reaction was continuedfor another 1.5 h. The reaction mixture was cooled to room temperatureand the ethanol was evaporated under reduced pressure. The residue wasdissolved in ethyl acetate (100 mL), washed water (50 mL), brine (30mL), dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to afford crude product, which was purified by silica gelcolumn chromatography using 60% ethyl acetate in hexane to afford thetitle compound5-(4-chlorophenyl)-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-4(3H)-one(0.8 g, 68% yield) as yellow solid.

Calculated (M+H): 330.98; Found (M+H): 331.2.

Step 2: ethyl2-(5-(4-chlorophenyl)-4-oxo-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetate

To a mixture of5-(4-chlorophenyl)-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-4(3H)-one(0.4 g, 1.21 mmol) and potassium carbonate (0.5 g, 3.63 mmol) in acetone(50 mL) was added ethyl 2-bromoacetate (0.26 g, 2.42 mmol) at roomtemperature. The reaction mixture was heated at 55° C. for 4 h. Themixture was allowed to cool to room temperature, filtered and thefiltrate was concentrated under reduced pressure to afford crudeproduct, which was purified by silica gel column chromatography using15% ethyl acetate in hexane to afford the title compound ethyl2-(5-(4-chlorophenyl)-4-oxo-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetate(0.5 g, 98% yield) as colorless semisolid.

Calculated (M+H): 417.02; Found (M+H): 417.0.

Step 3:2-(5-(4-chlorophenyl)-4-oxo-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-3(4H)-yl)aceticAcid

To a suspension of ethyl2-(5-(4-chlorophenyl)-4-oxo-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-3(4H)-yl)acetate(0.5 g, 1.20 mmol) in tetrahydrofuran:water mixture (10 mL, 1:1) wasadded lithium hydroxide monohydrate (0.15 g, 3.61 mmol) at 0° C. Theresulting suspension was gradually allowed to warm to room temperatureand stirred for 3 h. The reaction mixture was cooled to 0° C. andacidified with 1.5M hydrochloric acid solution to pH 2 to 3. Theprecipitated product was filtered, washed with water and dried to obtainthe title compound2-(5-(4-chlorophenyl)-4-oxo-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-3(4H)-yl)aceticacid (0.4 g, 87% yield) as a colorless solid.

Calculated (M+H): 388.89; Found (M+H): 388.4.

Step 4:5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2-(trifluoromethyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one

To a solution of2-(5-(4-chlorophenyl)-4-oxo-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-3(4H)-yl)aceticacid (0.1 g, 0.26 mmol) in dichloromethane (20 mL) were added3,3-difluoroazetidine hydrochloride (0.033 g, 0.26 mmol) andtriethylamine (0.18 mL, 1.28 mmol) at room temperature. The reactionmixture was cooled to 0° C. and 1-propanephosphonic anhydride (T₃P)(0.32 mL, 0.51 mmol, 50% solution in ethyl acetate) was added. Then thereaction mixture was allowed to warm to room temperature and stirred for6 h. The mixture was diluted with dichloromethane (50 mL), washed withwater (2×25 mL), brine solution (25 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford crude product,which was purified by silica gel column chromatography using 30% ethylacetate in hexane as eluent to afford the title compound5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2-(trifluoromethyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one(0.087 g, 73% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.10 (s, 1H), 7.63 (d, J=8.4 Hz, 2H),7.48 (d, J=8.4 Hz, 2H), 5.01 (s, 2H), 4.52-4.49 (m, 2H), 4.32-4.29 (m,2H).

Calculated (M+H): 464.02, Found (M+H): 464.0.

HPLC purity: 99.70%.

Biological Example

HEK293 cells with constructs conferring stable expression of the GRIN1gene and tetracycline-inducible expression of the GRIN2B gene (Chantest,Cleveland, Ohio) are grown to ˜75% confluence in tissue culture flasksat 37° C., 5% CO₂. NR2B expression is induced by overnight incubationwith 0.3-0.4 μg/ml tetracycline in the presence of 2.5 mM ARL-15896 at37° C., followed by moving to 30° C. for 3-5 hours. Cells are nextharvested using TripleExpress™ (Life Technologies, Carlsbad, Calif.)according to the manufacturer's instructions, first removing culturemedium, rinsing with Dulbecco's phosphate buffered saline (Ca²⁺ andMg²⁺-free), and then adding the TripleExpress™ reagent. Harvested cellsare spun down, washed twice in Ca²⁺- and Mg²⁺-free Hank's Balanced SaltSolution with 20 mM HEPES and 10 mM glucose, pH 7.4 (HHnoCa solution),and counted with viability assessed using Trypan Blue. Cells are loadedwith fluo-8 Ca²⁺-sensitive dye in HHnoCa solution according to themanufacturer's directions (AAT Bioquest, Sunnyvale, Calif.), incubatingat 37° C. for 20 minutes followed by 25 minutes at 22-25° C. After awash in HHnoCa to remove extracellular dye, cells are resuspended inHHnoCa and plated at 2×10⁷-3×10⁷ cells per well in a volume of 25μl/well in 384 well black-wall, clear bottom plates (Hamamatsu,Middlesex, N.J.). Plates are then centrifuged to create a monolayer inthe wells and stored in the dark until used.

Prior to analysis, compound plates are prepared with each compound at 6×the final desired concentration. From stock solutions at 10 mM in 100%DMSO, compounds are spotted in the desired amounts using an ECHO liquidhandler (Labcyte, Sunnyvale, Calif.) into wells of a 384-well plate andthen diluted with 50 μl of HHnoCa containing 750 nM Ro 25-6981 and 120μM 5,7-dichlorokynurenic acid (both purchased from Tocris Bioscience(Bristol, England) and maintained as 10 mM stock solutions in 100%DMSO). To insure complete compound dissolution, these plates are thenplaced in an orbital shaker for at least one hour. Also prepared priorto the assay is a co-agonist plate containing HHnoCa with 240 μMglutamate, 2.4 mM glycine, and 7.2 mM CaCl₂, which is 2.4× the desiredfinal concentration of each reagent. Both the compound plate andco-agonist plate are 384-well polypropylene plates from Thermo FisherScientific, Waltham, Mass.

The assay is performed by first adding 10 μl solution from each well ofthe compound plate described above to the cell plate using a CyBiWellliquid handler (Analytik Jena AG, Jena, Germany), followed by 10 minutespre-incubation in the dark. Cell plates are then loaded onto a HamamatsuFDSS 6000 plate reader. After a 30-second baseline, 25 μl is added toeach well from the co-agonist plate, and the fluorescence signal isrecorded for another 2 minutes. FDSS software applies shading andautofluorescence correction, and resultant raw fluorescence measurementsare exported in the form of a fluorescence ratio for each well to itsown reading at time zero in the experiment. In each plate, negativecontrol wells consist of wells where Ro 25-6981 and 5,7dichlorokynurenic acid are present and co-agonist is applied in theabsence of any added assay compound. Under these conditions, the Ca²⁺response to co-agonist is suppressed. Positive control wells alsopresent in each plate contain 5,7 dichlorokynurenic acid but no Ro25-6981, so that co-agonist addition results in a large Ca²⁺ response.Compounds tested are evaluated on the basis of their ability to reversethe suppression of the Ca²⁺ response mediated by Ro 25-6981, which isquantified as % reversal=100*(R−R_(neg))/(R_(pos)−R_(neg)) where R isthe fluorescence ratio for the test compound at the end of theexperiment and R_(neg) and R_(pos) are the end ratios for the negativeand positive controls, respectively. Using this equation, a compoundwould return 0% if it had no effect on the Ro 25-6981-mediatedsuppression of Ca²⁺ flux, whereas a compound that entirely reversed theeffect of Ro 25-6981 (to the level of co-agonist stimulation) wouldreturn 100%.

The results of the above assay are shown in Table 1.

TABLE 1 Ex. Avg Response No. IUPAC Name Recovered (%) 155-(3,4-dichlorophenyl)-3-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- 103oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one 145-(3-chloro-4-fluorophenyl)-3-[2-(3-fluoro-3-methylazetidin-1-yl)- 1652-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one 135-(3-chloro-4-fluorophenyl)-3-{2-[3-fluoro-3- 141(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one 125-(3-chloro-4-fluorophenyl)-3-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2- 149oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one 115-(3,4-dichlorophenyl)-3-[2-(3-fluoro-3-methylazetidin-1-yl)-2- 152oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one 105-(3,4-dichlorophenyl)-3-{2-[3-fluoro-3-(fluoromethyl)azetidin-1- 121yl]-2-oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one 205-[4-chloro-3-(trifluoromethyl)phenyl]-3-[3-(3,3-difluoroazetidin-1- −1yl)-3-oxopropyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one 95-(3-chloro-4-fluorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2- 49oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one 65-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-(3,3-difluoroazetidin-1- 62yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one 195-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2- 5methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one 215-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2- 0(trifluoromethyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one 185-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-6- 11methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one 83-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-5-(4-methylphenyl)- 53H,4H-thieno[2,3-d]pyrimidin-4-one 73-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-5-(4-fluorophenyl)- 63H,4H-thieno[2,3-d]pyrimidin-4-one 53-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-5-[4- 11(trifluoromethyl)phenyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one 163-[2-(azetidin-1-yl)-2-oxoethyl]-6-(4-chlorophenyl)-3H,4H- 23thieno[2,3-d]pyrimidin-4-one 176-(4-chlorophenyl)-3-[2-(3-methoxyazetidin-1-yl)-2-oxoethyl]- 243H,4H-thieno[2,3-d]pyrimidin-4-one 45-(4-chlorophenyl)-3-[2-(3-methoxyazetidin-1-yl)-2-oxoethyl]- 13H,4H-thieno[2,3-d]pyrimidin-4-one 35-(4-chlorophenyl)-3-(2-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-2- 0oxoethyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one 25-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]- 73H,4H-thieno[2,3-d]pyrimidin-4-one 13-[2-(azetidin-1-yl)-2-oxoethyl]-5-(4-chlorophenyl)-3H,4H- 2thieno[2,3-d]pyrimidin-4-one

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those itemslisted below, are hereby incorporated by reference in their entirety forall purposes as if each individual publication or patent wasspecifically and individually incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification. The full scope of the inventionshould be determined by reference to the claims, along with their fullscope of equivalents, and the specification, along with such variations.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in this specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained by the present invention.

1. A compound represented by Formula I:

and pharmaceutically acceptable salts, stereoisomers and prodrugsthereof, wherein: n is 1 or 2; R¹ and R² are each independently selectedfrom the group consisting of hydrogen, halogen, hydroxyl, NR^(a)R^(b),C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, and C₃₋₆cycloalkoxy; whereinC₁₋₄ alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, and C₃₋₆cycloalkoxy may beoptionally substituted with one, two or three substituents eachindependently selected from halogen, hydroxyl, cyano, and NR^(a)R^(b);or R¹ and R², together with the carbon to which they are attached form:a 4-6 membered saturated heterocyclic ring having one or two heteroatomsselected from the group consisting of O, S(O)_(w) (wherein w is 0, 1 or2) and NR^(a); or a 3-6 membered saturated carbocyclic ring; wherein theheterocyclic ring may optionally be substituted on carbon by one, two ormore substituents each selected from the group consisting of phenyl(optionally substituted by one, two or three halogens), C₃-C₆cycloalkyl(optionally substituted by one, two or three halogens), C₁₋₆alkoxy(optionally substituted by one, two or three halogens), C₁₋₆alkyl(optionally substituted by one, two or three halogens), and oxo; and ona carbon that is not bound to a heteroatom, by halogen, cyano,—NR^(a)R^(b) and hydroxyl; and the carbocyclic ring may optionally besubstituted by one, two or more substituents each selected from thegroup consisting of: phenyl (optionally substituted by one, two or threehalogens), C₃-C₆cycloalkyl (optionally substituted by one, two or threehalogens), C₁₋₆alkoxy (optionally substituted by one, two or threehalogens), C₁₋₆alkyl (optionally substituted by one, two or threehalogens), oxo, halogen, cyano, —NR^(a)R^(b) and hydroxyl; R³ isselected from the group consisting of phenyl, naphthyl, heteroaryl,heterocyclyl and C₃₋₆cycloalkyl; wherein R³ may optionally besubstituted with one, two or three substituents each independentlyselected from C₁₋₄alkyl, halogen, hydroxyl, cyano, C₁₋₄alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂—, NR^(a)R^(b), C(O)OH,C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl; and wherein C₁₋₄alkyl,C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,and C₁₋₆alkylcarbonyl may be optionally substituted by one or moresubstituents each independently selected from halogen, hydroxyl, cyano,and NR^(a)R^(b); R⁶⁶ and R⁶⁷ are each independently selected from thegroup consisting of hydrogen, halogen, C₁₋₄alkyl (optionally substitutedby one, two, three substituents selected from halogen, hydroxyl, cyanoand NR^(a)R^(b)), and phenyl (optionally substituted by one, two orthree halogens); and R^(a) and R^(b) are independently selected, foreach occurrence, from the group consisting of hydrogen and C₁₋₃alkyl; orR^(a) and R^(b), together with the nitrogen to which they are attached,form a 4-6 membered heterocyclic ring which may have an additionalheteroatom selected from O, S, or N.
 2. The compound of claim 1, whereinn is
 1. 3. The compound of claim 1, wherein R¹ and R² are eachindependently selected from the group consisting of hydrogen, halogen,C₁₋₃alkyl, and C₁₋₃alkoxy; wherein C₁₋₃alkyl and C₁₋₃alkoxy mayoptionally be substituted by one, two or three halogens.
 4. The compoundof claim 3, wherein R¹ and R² are each independently selected from thegroup consisting of hydrogen, fluorine, C₁₋₃alkyl and methoxy; whereinC₁₋₃alkyl may optionally be substituted by one, two or three fluorineatoms.
 5. The compound of claim 1, wherein R³ is selected from the groupconsisting of phenyl and heteroaryl; wherein R³ may optionally besubstituted with one, two or three substituents each independentlyselected from the group consisting of C₁₋₄alkyl, halogen, hydroxyl,cyano, C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂—, NR^(a)R^(b),C(O)OH, C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl; wherein C₁₋₄alkyl,C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,and C₁₋₆alkylcarbonyl may be optionally substituted by one or moresubstituents each independently selected from halogen, hydroxyl, cyano,and NR^(a)R^(b).
 6. The compound of claim 5, wherein R³ is phenyl,pyrimidinyl, pyrazinyl or pyridinyl, each optionally substituted by oneor two substituents each independently selected from the groupconsisting of halogen and C₁₋₃alkyl (optionally substituted by one, twoor three halogens).
 7. The compound of claim 6, wherein R³ is phenyl,optionally substituted by one, two or three substituents eachindependently selected from the group consisting of fluorine, chlorine,bromine, CF₃, and C₁₋₄alkyl.
 8. The compound of claim 7, represented by:

wherein R³³ is selected from the group consisting of fluorine, chlorine,CF₃ and methyl; and wherein q is 0, 1, 2 or
 3. 9. The compound of claim1, wherein R⁶⁶ and R⁶⁷ are each independently selected from the groupconsisting of hydrogen and C₁₋₃alkyl; wherein C₁₋₃alkyl may optionallybe substituted by one, two, or three halogens.
 10. The compound of claim9, wherein R⁶⁶ and R⁶⁷ are each independently selected from the groupconsisting of hydrogen, methyl, and CF₃.
 11. A compound represented byFormula II:

and pharmaceutically acceptable salts, stereoisomers and prodrugsthereof, wherein: R¹ and R² are each independently selected from thegroup consisting of hydrogen, halogen, hydroxyl, NR^(a)R^(b), C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, and C₃₋₆cycloalkoxy; wherein C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, and C₃₋₆cycloalkoxy may be optionallysubstituted with one, two or three substituents each independentlyselected from halogen, hydroxyl, cyano, and NR^(a)R^(b); R³ is selectedfrom the group consisting of phenyl, naphthyl, heteroaryl, heterocyclyland C₃₋₆cycloalkyl; wherein R³ may optionally be substituted with one,two or three substituents each independently selected from C₁₋₄alkyl,halogen, hydroxyl, cyano, C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂—,NR^(a)R^(b), C(O)OH, C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl; andwherein C₁₋₄alkyl, C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkyl-S(O)₂—, and C₁₋₆alkylcarbonyl may be optionally substituted byone or more substituents each independently selected from halogen,hydroxyl, cyano, and NR^(a)R^(b); R⁶⁶ and R⁶⁷ are each independentlyselected from the group consisting of hydrogen, halogen, C₁₋₄alkyl(optionally substituted by one, two, three substituents selected fromhalogen, hydroxyl, cyano and NR^(a)R^(b)), and phenyl (optionallysubstituted by one, two or three halogens); and R^(a) and R^(b) areindependently selected, for each occurrence, from the group consistingof hydrogen and C₁₋₃alkyl; or R^(a) and R^(b), together with thenitrogen to which they are attached, form a 4-6 membered heterocyclicring which may have an additional heteroatom selected from O, S, or N.12. The compound of claim 11, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen, halogen, C₁₋₃alkyl, andC₁₋₃alkoxy; wherein C₁₋₃alkyl and C₁₋₃alkoxy may optionally besubstituted by one, two or three halogens.
 13. The compound of claim 12,wherein R¹ and R² are each independently selected from the groupconsisting of hydrogen, fluorine, C₁₋₃alkyl and methoxy; whereinC₁₋₃alkyl may optionally be substituted by one, two or three fluorineatoms.
 14. The compound of claim 11, wherein R³ is selected from thegroup consisting of phenyl and heteroaryl; wherein R³ may optionally besubstituted with one, two or three substituents each independentlyselected from the group consisting of C₁₋₄alkyl, halogen, hydroxyl,cyano, C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl, R^(a)R^(b)N—SO₂—, NR^(a)R^(b),C(O)OH, C₁₋₄alkoxycarbonyl, and NR^(a)R^(b)carbonyl; wherein C₁₋₄alkyl,C₁₋₄alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,and C₁₋₆alkylcarbonyl may be optionally substituted by one or moresubstituents each independently selected from halogen, hydroxyl, cyano,and NR^(a)R^(b).
 15. The compound of claim 14, wherein R³ is phenyl,pyrimidinyl, pyrazinyl or pyridinyl, each optionally substituted by oneor two substituents each independently selected from the groupconsisting of halogen and C₁₋₃alkyl (optionally substituted by one, twoor three halogens).
 16. The compound of claim 15, wherein R³ is phenyl,optionally substituted by one, two or three substituents eachindependently selected from the group consisting of fluorine, chlorine,bromine, CF₃, and C₁₋₄alkyl.
 17. The compound of claim 16, representedby:

wherein R³³ is selected from the group consisting of fluorine, chlorine,CF₃ and methyl; and wherein q is 0, 1, 2 or
 3. 18. The compound of claim11, wherein R⁶⁶ and R⁶⁷ are each independently selected from the groupconsisting of hydrogen and C₁₋₃alkyl; wherein C₁₋₃alkyl may optionallybe substituted by one, two, or three halogens.
 19. The compound of claim18, wherein R⁶⁶ and R⁶⁷ are each independently selected from the groupconsisting of hydrogen, methyl, and CF₃.
 20. A compound selected fromthe group consisting of:5-(3,4-dichlorophenyl)-3-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(3-chloro-4-fluorophenyl)-3-[2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(3-chloro-4-fluorophenyl)-3-{2-[3-fluoro-3-(fluoromethyl)azetidin-1-yl]-2-oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(3-chloro-4-fluorophenyl)-3-[2-(3-ethyl-3-fluoroazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(3,4-dichlorophenyl)-3-[2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(3,4-dichlorophenyl)-3-{2-[3-fluoro-3-(fluoromethyl)azetidin-1l-yl]-2-oxoethyl}-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[3-(3,3-difluoroazetidin-1-yl)-3-oxopropyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(3-chloro-4-fluorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2-methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-2-(trifluoromethyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-6-methyl-3H,4H-thieno[2,3-d]pyrimidin-4-one;3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-5-(4-methylphenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one;3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-5-(4-fluorophenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one;3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-5-[4-(trifluoromethyl)phenyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;3-[2-(azetidin-1-yl)-2-oxoethyl]-6-(4-chlorophenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one;6-(4-chlorophenyl)-3-[2-(3-methoxyazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(4-chlorophenyl)-3-[2-(3-methoxyazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(4-chlorophenyl)-3-(2-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-2-oxoethyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one;5-(4-chlorophenyl)-3-[2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl]-3H,4H-thieno[2,3-d]pyrimidin-4-one;3-[2-(azetidin-1-yl)-2-oxoethyl]-5-(4-chlorophenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one;and pharmaceutically acceptable salts thereof.
 21. A pharmaceuticallyacceptable composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 22. A method of treating apatient suffering from a neuropsychiatric disorder comprisingadministering a compound of claim 1 or a composition of claim 21 to thepatient.
 23. The method of claim 22, wherein the neuropsychiatricdisorder is selected from schizophrenia, depression, an autism spectrumdisorder, and Rett syndrome.